Excessive dietary sodium intake augments long-term risk of atrial fibrillation in older adults with hyperglycemia: A community-based prospective cohort study.

AIM: Studies investigating the association between sodium intake and new-onset atrial fibrillation (AF) have come to controversial results. This study aimed to assess the effect of excessive sodium intake on new-onset AF in individuals with hyperglycemia. METHODS: Between April 2007 and November 2011, 2841 community-dwelling individuals aged 60 years and older were recruited from the Shandong area, China. Dietary sodium intake was estimated using 24-hour urine collection within seven consecutive days. Fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) were assessed. New-onset AF was diagnosed using ICD-10 with codes I48 (I48.0 - I48.9) during follow-up. RESULTS: The findings were that excessive sodium intake significantly and independently increased the risk of new-onset AF in older adults with hyperglycemia: hazard ratio (HR) 1.525 [95% confidence interval 1.147;2.029] adjusted P = 0.004. The risk of new-onset AF increased by 29.3% (HR 1.293 [1.108;1.509] adjusted P = 0.001) with a one-standard deviation increase in sodium intake. Excessive sodium intake synergistically interacted with hyperglycemia on the increased risk of new-onset AF (HR 1.599 [1.342;1.905] adjusted P < 0.001 for FPG and HR 1.516 [1.271;1.808] adjusted P < 0.001 for HbA1c). CONCLUSION: Our findings indicate that excessive sodium intake independently enhances the risk of new-onset AF among patients with hyperglycemia. A sodium-restricted diet may perhaps result in a multiplier effect on reducing the risk of new-onset AF.

Primary tumor location impacts survival in colorectal cancer patients after primary resection: a population­based propensity score matching cohort study.

Background: Right-sided colon cancers (R-CCs) are associated with worse outcomes compared to left-sided colon cancers (L-CCs). This study aimed to investigate whether a difference in survival existed among R-CC, L-CC, and rectal cancer (ReC) and subsequent liver metastasis. Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) database for 2010-2015 was used to identify colorectal cancer (CRC) patients who underwent surgical resection of primary disease. Propensity score adjustment and Cox regression models were used to identify risk factors and prognostic factors of primary tumor location (PTL). Kaplan-Meier curve analysis and the log-rank test were used to evaluate overall survival (OS) of CRC patients. Results: Our results showed that among the 73,350 included patients, 49% were R-CC, 27.6% L-CC, and 23.1% ReC. Before propensity score matching (PSM), the OS of the R-CC group was significantly lower than that of the L-CC and ReC groups (P<0.05). However, the clinicopathological characteristics, including gender, tumor grade, tumor size, marital status, tumor (T) stage, node (N) stage, and carcinoembryonic antigen (CEA), were significantly unbalanced among the 3 groups (P<0.05). After 1:1 PSM, 8670 patients were effectively screened out in each group. The differences in clinicopathological characteristics among the 3 groups were significantly reduced, and baseline distribution characteristics such as gender, tumor size, and CEA were significantly improved after matching (P>0.05). Survival was higher in the left-side group when evaluated by tumor sidedness, and ReC patients had the highest median survival (114.3 months). Right-sided cancer patients had the worst prognosis in both PTL and sidedness analyses, with a median survival of 76.6 months. Among CRC patients with synchronous liver metastases, adjustment by inverse propensity weight and propensity score and analysis of OS yielded similar results and had more significant stratification results. Conclusions: In conclusion, R-CC has a worse survival prognosis compared to L-CC and ReC, and they are fundamentally different tumors that have distinct effects on CRC patients with liver metastases.

High salt intake damages myocardial viability and induces cardiac remodeling via chronic inflammation in the elderly.

Background: The heart is an important target organ for the harmful effects of high dietary salt intake. However, the effects and associations of high salt intake on myocardial viability, cardiac function changes, and myocardial remodeling are unclear. Methods: A total of 3,810 participants aged 60 years and older were eligible and enrolled from April 2008 to November 2010 and from August 2019 to November 2019 in the Shandong area of China. Salt intake was estimated using 24-h urine collection consecutively for 7 days. Myocardial strain rates, cardiac function and structure, and serum high-sensitivity C-reactive protein (hsCRP) levels were assessed. Participants were classified into low (n = 643), mild (n = 989), moderate (n = 1,245), and high (n = 933) groups, corresponding to < 6, 6-9, 9-12, and >12 g/day of salt intake, respectively, depending on the salt intake estimation. Results: The global early diastolic strain rate (SRe) and late diastolic strain rate (SRa) in the high group were 1.58 ± 0.26, 1.38 ± 0.24. respectively, and significantly lower compared with the low, mild, and moderate groups (all P < 0.05). The global systolic strain rate (SRs) in the high group was -1.24 ± 0.24, and it was higher than those in the low, mild, and moderate groups (all P < 0.05). Salt intake was independently and positively correlated with global SRs, Tei index, and the parameters of left ventricular structure separately; negatively correlated with global SRe and SRa, left ventricular short axis shortening rate, left ventricular ejection fraction after adjusting for confounders (all P adjusted < 0.001). Hayes process analyses demonstrated that the mediating effects of hsCRP on global SRe, SRa, and SRs; Tei index; and left ventricular remodeling index were -0.013 (95% CI: -0.015 to -0.010), -0.010 (-0.012 to -0.008), 0.008 (0.006-0.010), 0.005 (0.003-0.006), and 0.010 (0.009-0.012), respectively (all P adjusted < 0.001). Conclusion: Our data indicate that excess salt intake is independently associated with the impairment in myocardial viability and cardiac function, as well as myocardial remodeling. Chronic inflammation might play a mediating role in the association between high salt intake and cardiac function damage and myocardial remodeling.

Epigallocatechin-3-gallate prevents inflammation and diabetes -Induced glucose tolerance through inhibition of NLRP3 inflammasome activation.

Epigallocatechin-3-gallate (EGCG), the primary polyphenol component of green tea, has been shown to inhibit both oxidation and inflammation. However, the exact mechanism through which EGCG exhibits anti-inflammatory effects remains unclear. In this study, we assessed the potential pathways by which EGCG regulates NLRP3 inflammasome activity in vitro. We found that EGCG inhibits caspase-1 activation and IL-1ß secretion by suppressing NLRP3 inflammasome activation in mouse bone marrow-derived macrophages (BMDMs). EGCG was also observed to block NLRP3-mediated ASC speckle formation and to alleviate pyroptosis in BMDMs. In addition, EGCG treatment could improve high-fat diet (HFD)-induced glucose tolerance and prevent NLRP3 inflammasome-dependent inflammation in a mouse model of HFD-induced type 2 diabetes (T2D). Taken together, our results show that EGCG is a general inhibitor of NLRP3 inflammasome activation and administration of EGCG in T2D mice could improve glucose tolerance in vivo.

Study of Top-down and Bottom-up Approaches by Using Design of Experiment (DoE) to Produce Meloxicam Nanocrystal Capsules.

In order to investigate the correlation among energy input-related, drug-related, and stabilizer-related aspects for both top-down and bottom-up nanocrystal production, meloxicam nanosuspensions (NS) were produced by using three different methods (low-energy wet milling, high-pressure homogenization, and precipitation) and each method was optimized by using design of experiment (DoE). Box-Behnken design of 3 factors and 3 levels was applied for the optimization of each method. All the three models were found to be significant and the optimized process parameters were used for production of NS, respectively. Interestingly, by comparison of the top-down and bottom-up approaches, the influence of energy input (homogenization pressure or milling speed) from the instruments seemed not significant for top-down compared with bottom-up for this drug. Different mechanisms of homogenization (relatively high energy zone) and milling (relatively low energy zone) led to obtained various significant correlations for each method. Capsules containing nanocrystals were successfully produced by using a novel method applying NS (after wet bead milling and homogenization processes) as wetting agent for direct capsuling and showed superiority regarding as dissolution rate compared with the traditional two-step method (freeze-dried powder used for capsuling as the first step). Different NS preparation methodologies proved to have a direct influence on the following capsuling process and consequently, in the dissolution rate. This study also proved that residual DMSO in nanosuspension after precipitation process could affect the freeze-drying process, which might further alter the redispersion and influence the downstream processes.

Advanced modification of drug nanocrystals by using novel fabrication and downstream approaches for tailor-made drug delivery.

Drug nanosuspensions/nanocrystals have been recognized as one useful and successful approach for drug delivery. Drug nanocrystals could be further decorated to possess extended functions (such as controlled release) and designed for special in vivo applications (such as drug tracking), which make best use of the advantages of drug nanocrystals. A lot of novel and advanced size reduction methods have been invented recently for special drug deliveries. In addition, some novel downstream processes have been combined with nanosuspensions, which have highly broadened its application areas (such as targeting) besides traditional routes. A large number of recent research publication regarding as nanocrystals focuses on above mentioned aspects, which have widely attracted attention. This review will focus on the recent development of nanocrystals and give an overview of regarding modification of nanocrystal by some new approaches for tailor-made drug delivery.

Emerging role of HOX genes and their related long noncoding RNAs in lung cancer.

The transcription factor homeobox (Hox) proteins are the master regulator for the embryonic development. Studies have identified new functions for HOX in the regulation of metabolism and other primary cellular processes in humans. Their dysregulation has been observed in a variety of cancers and accumulating evidence has revealed the crucial role of HOX in cancer progression, metastasis, and resistance to therapy. HOX-related long non-coding RNAs (lncRNAs) became the most attracting lncRNAs recently that play critical role in gene regulation and chromatin dynamics in cancers. In this review, we explore the roles of HOX and their related lncRNAs in lung cancer, indicating HOX genes as potential therapeutic targets in lung cancer.

Long non-coding RNA HOXD-AS1 in cancer.

Cancer is one of the leading causes of death worldwide with a high risk of incidence and mortality. Long non-coding RNAs (lncRNAs) have been shown to participate in various biological processes, including tumorigenesis and progression. The HOXD-AS1 (also known as HAGLR and Mdgt) gene is located between the HOXD1 and HOXD3 genes in the HOXD cluster and has been reported to play a critical role in the development and progression of cancers. This review summarizes the current knowledge on the biological functions and mechanisms of HOXD-AS1 in different human cancers, including bladder, cervical, colorectal, gastric, ovarian, and prostate cancers, glioma, hepatocellular carcinoma, melanoma, osteosarcoma, and non-small cell lung cancer. The aberrant expression of HOXD-AS1 in these cancers was related with clinical features of patients with cancers. HOXD-AS1 regulates the growth, invasion, and migration of tumor cells through different underlying mechanisms. In conclusion, HOXD-AS1 may be considered as a promising diagnostic/prognostic biomarker or a novel therapeutic target for cancers.

Deubiquitinase USP48 promotes ATRA-induced granulocytic differentiation of acute promyelocytic leukemia cells.

All-trans retinoic acid (ATRA) has been used for the treatment of acute promyelocytic leukemia (APL). However, its molecular mechanisms of action are unclear. Ubiquitin-specific protease 48 (USP48) is a deubiquitinase enzyme that can post-translationally remove ubiquitin molecules from substrates. In the present study, the role of USP48 in ATRA-induced differentiation of APL cells was studied. The expression of USP48 decreased following ATRA treatment. Functionally, overexpression of USP48 using electroporation-mediated delivery inhibited the proliferation of APL cells and promoted ATRA-mediated differentiation. The inverse observations were made upon siRNA-mediated knockdown of USP48. Furthermore, the expression of USP48 was increased in the nucleus upon ATRA exposure for ≤24 h, suggesting that USP48 was translocated into the nucleus. Interestingly, regulation of p65, a substrate of USP48, did not contribute to the downstream mechanism of ATRA-induced differentiation of APL cells. In addition, upstream mechanistic studies demonstrated that the expression of USP48 was regulated by microRNA-301a-3p. In conclusion, the present study highlights the function of USP48 in the ATRA-induced granulocytic differentiation of APL cells and provides a theoretical basis for identifying novel targets for differentiation therapy of APL.

Prognostic role of microRNA-155 in patients with leukemia: A meta-analysis.

BACKGROUND: Recent studies have shown that microRNA-155 (miR-155) is correlated with clinical outcomes of leukemia. This meta-analysis explores to evaluate the prognostic value of miR-155 for survival in patients with leukemia. METHODS: Eligible studies were searched from PubMed and EMBASE databases. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for overall survival (OS), disease-free survival, event-free survival, progression-free survival and treatment-free survival were extracted, if available. Pooled HRs and 95% CIs were used to study any correlation between miR-155 and survival. RESULTS: 11 studies from 10 articles containing 1718 leukemia patients were included. Data showed that the pooled HR for OS was 1.67 (95% CI: 1.44-1.95, P < 0.01). Subgroup analyses for OS showed that the pooled HRs and their 95% CIs were 1.68, 1.41-2.00 (P < 0.01) and 1.73, 1.25-2.41 (P < 0.01) for acute myeloid leukemia and chronic lymphoblastic leukemia, respectively. Furthermore, there was no significant heterogeneity or publication bias among the enrolled datasets. CONCLUSION: We conclude that high miR-155 expression was associated with shorter OS for leukemia patients, and that miR-155 might be a promising prognostic biomarker for this patient population.

Curcumin Suppresses IL-1ß Secretion and Prevents Inflammation through Inhibition of the NLRP3 Inflammasome.

Turmeric is traditionally used as a spice and coloring in foods. Curcumin is the primary active ingredient in the turmeric, and compelling evidence has shown that it has the ability to inhibit inflammation. However, the mechanism mediating its anti-inflammatory effects are not fully understood. We report that curcumin inhibited caspase-1 activation and IL-1ß secretion through suppressing LPS priming and the inflammasome activation pathway in mouse bone marrow-derived macrophages. The inhibitory effect of curcumin on inflammasome activation was specific to the NLRP3, not to the NLRC4 or the AIM2 inflammasomes. Curcumin inhibited the NLRP3 inflammasome by preventing K+ efflux and disturbing the downstream events, including the efficient spatial arrangement of mitochondria, ASC oligomerization, and speckle formation. Reactive oxygen species, autophagy, sirtuin-2, or acetylated α-tubulin was ruled out as the mechanism by which curcumin inhibits the inflammasome. Importantly, in vivo data show that curcumin attenuated IL-1ß secretion and prevented high-fat diet-induced insulin resistance in wide-type C57BL/6 mice but not in Nlrp3-deficient mice. Curcumin also repressed monosodium urate crystal-induced peritoneal inflammation in vivo. Taken together, we identified curcumin as a common NLRP3 inflammasome activation inhibitor. Our findings reveal a mechanism through which curcumin represses inflammation and suggest the potential clinical use of curcumin in NLRP3-driven diseases.

Systematical Investigation of Different Drug Nanocrystal Technologies to Produce Fast Dissolving Meloxicam Tablets.

Three different methods, i.e., high-pressure homogenization, wet bead milling, and a combination approach of freeze-drying and high-pressure homogenization, were used to produce meloxicam nanosuspensions, respectively. Wet bead milling led to the nanosuspensions with smallest particle size (88 nm) after 4 h and optimal dissolution performances. Freeze-dried meloxicam powder could highly improve the size reduction efficiency compared to the unmodified drug and particle size of the freeze-dried sample could be reduced to 342 nm after only one homogenization cycle at 1000 bar. The polymorphism transition and change of the particle morphology after the lyophilization might be important reasons to affect the nanosizing processes. Interestingly, the tablets prepared by using nanosuspensions from homogenizer and combination process showed faster dissolution in the first 20 min than the bead milling nanocrystal tablets.

Preparation Nanocrystals of Poorly Soluble Plant Compounds Using an Ultra-Small-Scale Approach.

The usage of downscaling technology for producing nanosuspensions/nanocrystals can be beneficial for formulation development, which has attracted increased attention recently. An ultra-small bead milling method (5 mg compound per batch, smallest scale to date) was tested to produce nanocrystals of four poorly soluble plant compounds, i.e., quercetin, rutin, resveratrol, and hesperidin. A particle size of ranged from 200 to 500 nm was obtained for nanosuspensions of four compounds and the stabilizer selection could be achieved within 2 h by using this ultra-small bead milling method. Six months stability was observed for selected samples. In addition, the scalability of the ultra-small lab-scale milling was confirmed when it was conducted under optimal conditions. A simple and fast ultra-small-scale approach for nanosuspension production was established. Freeze-drying was applied to convert nanosuspensions into solid forms. Finally, freeze-dried intermediates with good redispersity and physical stability were obtained, which could be used for further application.

A drug-loaded nanoscale metal-organic framework with a tumor targeting agent for highly effective hepatoma therapy.

Drug delivery systems with targeting agents for precise drug release in cancer therapy are very significant and important. Herein, we report the rational design and synthesis of a DOX (doxorubicin) loaded UiO-68-type of nanoscale metal-organic framework (NMOF) with a tumor targeting agent (folic acid, FA), DOX@UiO-68-FA (3), as a multifunctional drug delivery system for hepatoma (Hep G2) therapy via tail-vein injection. Compared to free DOX, FA-unloaded DOX@Mi-UiO-68 (2), 3 exhibits a much higher antitumor efficacy, which was confirmed by cell imaging, standard 3-(4,5-dimethylthiahiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) proliferation and in vivo experiments.

Silencing of CD59 enhanced the sensitivity of HT29 cells to 5-Fluorouracil and Oxaliplatin.

Complement regulatory proteins (CD55 and CD59) were known to be expressed in many tumors and tumor cell lines including colorectal carcinoma, and were proposed as immunotherapy targets, however whether knocking down of CD55 and CD59 will affect the sensitivity of HT-29 cells to chemotherapy drugs for example, 5-Fluorouracil and Oxaliplatin and their possible mechanisms haven't been studied. To address this question, SiRNAs targeting CD55 and CD59 were chemically synthesized and transfected into HT-29 cells by lipofectamine. HT-29 growth curves of CD55 and CD59 knockdown cells were detected by MTT assay, HT29 inhibition curves to chemotherapy drugs (5-Fu and Oxaliplatin) were also assayed, in addition, chemotherapy sensitivity changes of HT29 affected by CD55 and CD59 knockdown were equally detected. Complement mediated lysis was examined by calcein-AM. We found that silencing CD59 in HT-29 cells could significantly enhance their sensitivity to 5-FU (P < 0.05) and Oxaliplatin (P < 0.05), and significantly reduced their IC50 concentration. On the contrary, knocking down of CD55 could inhibit HT-29 growth (P < 0.05). Mechanisms included increasing apoptosis rate of HT-29 by CD59 knocking down and G1/G0 blocking by silencing CD55. Our results thus shed light on the novel mechanism of chemotherapy resistance and provide an alternative strategy to overcome the resistance problem.

Combination of interferon-α and 5-fluorouracil induces apoptosis through mitochondrial pathway in hepatocellular carcinoma in vitro.

Many clinical reports have proven that the combination therapy of interferon-alpha plus 5-fluorouracil is remarkably effective for advanced hepatocellular carcinoma (HCC). However, the mechanism of this therapy is not well understood. Here, we demonstrated that the combination therapy synergistically inhibited the growth of Fas-negative HCC cells, arrested cell-cycle progression and induced apoptosis. Moreover, the combination therapy significantly increased the protein expression of caspase-8, activated Bid and cytochrome c. Meanwhile, the expression of anti-apoptotic gene Bcl-xL was reduced and intracellular calcium elevated obviously during the early stage of treatment. Therefore, mitochondrial pathway was involved in the apoptosis of Fas-negative HCC cells induced by IFN-α/5-FU and Ca(2+) partially promoted the beneficial effect against HCC.

Influence of CXCR4/SDF-1 axis on E-cadherin/ß-catenin complex expression in HT29 colon cancer cells.

AIM: To study the influence of CXCR4/stromal cell-derived factor-1 (SDF-1) axis on E-cadherin/ß-catenin complex expression in HT29 colon cancer cells and its underlying mechanisms. METHODS: Effect of SDF-1 on E-cadherin/ß-catenin expression was detected by immunocytochemistry. E-cadherin and ß-catenin mRNA expression levels were measured by reverse transcriptase-polymerase chain reaction. SDF-1-induced phosphorylation of phosphatidylinositol 3-kinase (PI3K)/AKT and ß-catenin was detected by Western blotting. RESULTS: The E-cadherin and ß-catenin mRNA expression levels in HT29 cells were lower 48 h after incubated with SDF-1 at the concentrations of 20 and 40 ng/mL (P<0.05). SDF-1-induced significant phosphorylation of PI3K/AKT and ß-catenin. AMD3100 and LY294002 inhibited the phosphorylation of PI3K/AKT and ß-catenin. CONCLUSION: SDF-1 down-regulates the E-cadherin/ß-catenin complex expression in HT29 cells by decreasing mRNA synthesis and increasing ß-catenin phosphorylation.

A novel tumor suppressor gene RhoBTB2 (DBC2): frequent loss of expression in sporadic breast cancer.

RhoBTB2 was isolated recently as a tumor suppressor gene from human chromosome 8p21.3. Although RhoBTB2 was found to be frequently lost in breast cancer lines, expression status of RhoBTB2 in sporadic breast cancer tissues and its clinical and prognostic value, however, remain unclear. Tissue samples from breast cancer patients and normal controls and cell samples from cell lines were collected and reverse transcription (RT)-PCR was used to monitor the presence of RhoBTB2 mRNA. The protein expression of RhoBTB2 was detected by immunohistochemical staining. Cumulative survival time was assessed by the Kaplan-Meier method and Cox regression model. We discovered that RhoBTB2 expression was lacking in a breast ductal epithelial carcinoma cell line T-47D but was expressed in other types of tumor cell lines and normal tissues we tested. The results from tissue samples showed that RhoBTB2 was absent in 60% of breast cancers on both the mRNA and protein level. The results from RT-PCR were completely uniform with those from immunohistochemistry. We demonstrated that loss of RhoBTB2 more frequently occurred in postmenopausal patients of age >or=50 yr old and in patients with infiltrating ductal carcinoma of the breast. The prognostic value of RhoBTB2 in breast cancers also be assessed by a long-term follow-up investigation and we found that patients with RhoBTB2-negative breast cancer were linked to poor clinical prognosis. Therefore, the loss of RhoBTB2 expression is a common occurrence in breast cancers and it is an important factor in the development and prognosis of sporadic breast cancer.

Effects of specific antisense oligonucleotide inhibition of Fas expression on T cell apoptosis induced by Fas ligand.

To investigate the effect of specific antisense oligodeoxynucleotide (ASODN) inhibition of Fas expression on T cell apoptosis induced by hepatocarcinoma cells. Fas receptor (Fas) and Fas ligand (FasL) expressed by the hepatocarcinoma cell line HepG2.2.15 and Jurkat T cells were detected by flow cytometry (FCM) and the ability of FasL-inducing T cell apoptosis was tested by co-culture assay in vitro with HepG2.2.15 cells and Jurkat T cells. The Jurkat cells were transfected with Fas-ASODN using lipofectin, and the effects of Fas-ASODN on Fas mRNA level, Fas expression on T cells surface, and apoptosis were investigated by RT-PCR, FCM and co-culture assay, respectively. It was found that HepG2.2.15 cells expressing functional FasL could induce the apoptosis of Jurkat cells as demonstrated by co-culture assays. After the Jurkat cells were transfected with Fas ASODN, the level of Fas mRNA, the expression rate of Fas and the apoptotic rate induced by hepatocarcinoma cells were all decreased. As a conclusion, it is evident that hepatocarcinoma cells expressing FasL can induce apoptosis in Fas-expressing T cells, indicating that transfection of Fas ASODN can partially convert the immune inhibitory condition induced by hepatocarcinoma cells.